MCAT Biochemistry - Lipid and Amino Acid Metabolism

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Dietary fat

consists mainly of triacylglycerols, with the remainder comprised of cholesterol, cholesteryl esters, phospholipids, and free fatty acids

Lipid digestion

minimal in the mouth and stomach; mostly occurs in small intestine

emulsification

mixing of two normally immiscible liquids; increases the surface area of the lipid, which permits greater enzymatic interaction and processing; aided by bile

bile

contains bile salts, pigments, and cholesterol; secreted by the liver and stored in the gallbladder

pancreas

secretes pancreatic lipase, colipase, and cholesterol esterase that hydrolyze the lipid components to 2-monoacylglycerol, free fatty acids, and cholesterol

micelles

clusters of amphipathic lipids that are soluble in the aqueous environment of the intestinal lumen; vital in digestion, transport, and absorption of lipid-soluble substances starting from the duodenum all the way to the end of the ileum

chylomicrons

lipoproteins; transport dietary triacylglycerols, cholesterol, and cholesteryl esters from intestine to tissues; highly soluble in both lymphatic fluid and blood; assembly occurs in intestinal lining

lacteals

vessels of the lymphatic system

thoracic duct

long lymphatic vessel that empties into the left subclavian vein at the base of the neck

hormone-sensitive lipase (HSL)

hydrolyzes triacylglycerols yielding fatty acids and glycerol in adipose tissues

activated by fall in insulin levels, epinephrine, cortisol

lipoprotein lipase (LPL)

necessary for the metabolism of chylomicrons and very-low-density lipoproteins; enzyme that can release free fatty acids from triacylglycerols in these lipoproteins

postabsorptive state

utilizing energy stores instead of food for fuel

albumin

carrier protein responsible for free fatty acid transport in blood

lipoproteins

Biochemical assembly whose purpose is to transport hydrophobic lipid molecules; named according to their density proportionate to the percentage of protein

apolipoproteins / apoproteins

proteins that bind lipids to form lipoproteins; receptor molecules and are involved in signaling

types of apolipoproteins

• apoA-I: activates LCAT, an enzyme that catalyzes cholesterol esterification

• apoB-48: mediates chylomicron secretion

• apoB-100: permits uptake of LDL by the liver

• apoC-II: activates lipoprotein lipase

• apoE: permits uptake of chylomicron remnants and VLDL by the liver

very low density lipoproteins (VLDL)

Transports triacylglycerols and fatty acids from liver to tissues; produced and assembled in liver cells; contain fatty acids that are synthesized from excess glucose or retrieved from chylomicron remnants

intermediate density lipoproteins (IDL, VLDL remnant)

when triacylglycerol is removed from VLDL; picks up cholesteryl esters from HDL to become LDL; reabsorbed by the liver by apolipoproteins on its exterior or further processed in the bloodstream; transition particle between triacylglycerol transport (associated with chylomicrons and VLDL) and cholesterol transport (associated with LDL and HDL)

low density lipoproteins (LDL)

Delivers cholesterol into cells for biosynthesis; cholesterol measured in blood

high density lipoproteins (HDL)

Picks up cholesterol accumulating in blood vessels; Delivers cholesterol to liver and steroidogenic tissues; Transfers apolipoproteins to other lipoproteins; synthesized in the liver and intestines and released as dense, protein- rich particles into the blood

Cholesterol

ubiquitous component of all cells in the human body; plays a major role in the synthesis of cell membranes, steroid hormones, bile acids, and vitamin D; derived from LDL or HDL or synthesised de novo

De novo synthesis of cholesterol

occurs in liver and is driven by acetyl-CoA and ATP

1. citrate shuttle carries mitochondrial acetyl-CoA into the cytoplasm, where synthesis occurs

2. NADPH supplies reducing equivalents

3. Synthesis of mevalonic acid in the smooth endoplasmic reticulum (SER) by 3-hydroxy-3-methylglutaryl (HMG) CoA reductase = rate-limiting step

inhibited by cholesterol

promoted by insulin and HMG-CoA reductase gene expression

Lecithin–cholesterol acyltransferase (LCAT)

enzyme found in the bloodstream that is activated by HDL apoproteins; adds a fatty acid to cholesterol produces soluble cholesteryl esters such as those in HDL

cholesteryl ester transfer protein (CETP)

HDL cholesteryl esters can be distributed to other lipoproteins like IDL, which becomes LDL by acquiring these cholesteryl esters

Fatty acids

long-chain carboxylic acids

carbons:double bonds

Saturated fatty acids

no double bonds; generally cis configuration

unsaturated fatty acids

one or more double bonds; largely essential

α-linolenic acid & linoleic acid

polyunsaturated fatty acids; important in maintaining cell membrane fluidity

omega (ω) numbering system

describes the position of the last double bond relative to the end of the chain and identifies the major precursor fatty acid

nontemplate synthesis

do not rely directly on the coding of a nucleic acid

Palmitic acid (palmitate)

primary end product of fatty acid synthesis

Fatty acid biosynthesis

occurs in the liver and occassionally in adipose tissue; products are subsequently transported to adipose tissue for storage; acetyl-CoA carboxylase and fatty acid synthase

stimulated by insulin

pyruvate dehydrogenase complex

produces Acetyl-CoA → couples with oxaloacetate to form citrate

citrate shuffle

moves citrate from inside mitochondria to cytoplasm

citrate lyase

splits citrate back into acetyl-CoA and oxaloacetate (returns to the mitochondrion to continue moving acetyl-CoA)

Acetyl-CoA carboxylase

activated in the cytoplasm for incorporation into fatty acids; rate-limiting enzyme of fatty acid biosynthesis; adds CO2 to acetyl-CoA to form malonyl-CoA

requires biotin and ATP

activated by insulin and citrate

Fatty acid / palmitate synthase

large multienzyme complex found in the cytosol; contains an acyl carrier protein (ACP); Eight acetyl-CoA groups are required; may then be elongated and desaturated, to a limited extent, using enzymes associated with the smooth endoplasmic reticulum

requires pantothenic acid (vitamin B5) and NADPH

activated by insulin

palmitate (16:0)

only fatty acid that humans can synthesize de novo.

Triacylglycerol (Triglyceride) Synthesis

the storage form of fatty acids; formed by attaching three fatty acids (as fatty acyl-CoA) to glycerol; primarily occurs in the liver

β-oxidation

Most fatty acid catabolism in the mitochondria; can be peroxisomal; reverses the process of fatty acid synthesis by oxidizing and releasing molecules of acetyl-CoA

inhibited by insulin

stimulated by glucagon

Steps of β-oxidation

1. Oxidation of the fatty acid to form a double bond

2. Hydration of the double bond to form a hydroxyl group

3. Oxidation of the hydroxyl group to form a carbonyl (β-ketoacid)

4. Splitting of the β-ketoacid into a shorter acyl-CoA and acetyl-CoA

continues until the chain has been shortened to two carbons, creating a final acetyl-CoA

odd numbers: odd-numbered fatty acids yield one acetyl- CoA and one propionyl-CoA → may eventually go on to make glucose

α-oxidation

catabolism of branched-chain fatty acids

ω-oxidation

in the endoplasmic reticulum; produces dicarboxylic acids

fatty-acyl-CoA synthetase

attaches fatty acids to CoA for metabolism → fatty acyl-CoA or acyl-CoA

Carnitine acyltransferase I

rate-limiting enzyme of fatty acid oxidation; transports long-chain fatty acids (14 to 20 carbons) into mitochondria (smaller chains diffuse freely)

propionyl-CoA carboxylase

Propionyl-CoA is converted to methylmalonyl-CoA

requires biotin (vitamin B7)

methylmalonyl-CoA mutase

Methylmalonyl-CoA is converted into succinyl-CoA; citric acid cycle intermediate and can also be converted to malate to enter the gluconeogenic pathway in the cytosol

requires cobalamin (vitamin B12)

Enoyl-CoA isomerase

rearranges cis double bonds at the 3,4 position to trans double bonds at the 2,3 position once enough acetyl-CoA has been liberated to isolate the double bond within the first three carbons; permits β-oxidation to proceed in monounstaurated fatty acids

2,4-dienoyl-CoA reductase

convert two conjugated double bonds to just one double bond at the 3,4 position, to form a trans 2,3 double bond in polyunsaturated fatty acids

ketone bodies

water-soluble molecules or compounds that contain the ketone groups produced from fatty acids by the liver; readily transported into tissues outside the liver, where they are converted into acetyl-CoA which then enters the citric acid cycle and is oxidized for energy

ex. acetoacetate and 3-hydroxybutyrate (β-hydroxybutyrate)

tissues that can use ketone bodies

Cardiac and skeletal muscle and the renal cortex; muscles during fasting (as fast as liver can produce, prevent accumulation), one week fasting - brain

Ketogenesis

production of ketone bodies; occurs in the mitochondria of liver cells when excess acetyl- CoA accumulates in the fasting state

HMG-CoA synthase

forms HMG-CoA

HMG-CoA lyase

breaks down HMG-CoA into acetoacetate, which can subsequently be reduced to 3-hydroxybutyrate; acetone is a minor side product that is formed but will not be used as energy

succinyl-CoA acetoacetyl-CoA transferase (thiophorase)

Acetoacetate picked up from the blood is oxidized to acetoacetyl-CoA in the mitochondria; enzyme absent in liver

Ketolysis

use of ketone bodies for energy; when ketones are metabolized to acetyl-CoA, pyruvate dehydrogenase is inhibited - spares essential protein from being metabolised into glucose

Proteolysis

breakdown of proteins; begins in the stomach with pepsin, continues with the pancreatic proteases trypsin, chymotrypsin, and carboxypeptidases A and B, completed by the small intestinal brush-border enzymes dipeptidase and aminopeptidase; → amino acids, dipeptides, and tripeptides that are absorbed through the luminal membrane by secondary active transport linked to sodium

urea cycle

amino groups removed by transamination or deamination constitute a potential toxin to the body in the form of ammonia; occurs in the liver

amino acid side chain metabolism

Basic amino acid side chains feed into the urea cycle

other side chains act like the carbon skeleton and produce energy through gluconeogenesis or ketone production